Poor Immune Responses of Newborn Rhesus Macaques to Measles Virus DNA Vaccines Expressing the Hemagglutinin and Fusion Glycoproteins

Polack, Fernando P.; Lydy, Shari L.; Lee, Sok Hyong; Rota, Paul A.; Bellini, William J.; Adams, Robert J.; Robinson, Harriet L.; Griffin, Diane E.

doi:10.1128/cvi.00394-12

Cited by 9 publications

(6 citation statements)

References 46 publications

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“…DNA vaccines have exhibited sub-optimal immunogenicity in non-human primate models [33,] and in human clinical trials [34], highlighting the need for more effective immune enhancement strategies. Delivery of DNA vaccine by EP and prime-boost immunization strategy have revealed encouraging results [18, 19].…”

Section: Discussionmentioning

confidence: 99%

Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons

Kumar

Nyakundi

Kariuki

et al. 2013

Vaccine

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Plasmodium falciparum Pfs25 antigen, expressed on the surface of zygotes and ookinetes, is one of the leading targets for the development of a malaria transmission-blocking vaccine (TBV). Our laboratory has been evaluating DNA plasmid based Pfs25 vaccine in mice and non-human primates. Previously, we established that in vivo electroporation (EP) delivery is an effective method to improve the immunogenicity of DNA vaccine encoding Pfs25 in mice. In order to optimize the in vivo EP procedure and test for its efficacy in more clinically relevant larger animal models, we employed in vivo EP to evaluate the immune response and protective efficacy of Pfs25 encoding DNA vaccine in nonhuman primates (Olive baboons, Papio anubis). The results showed that at a dose of 2.5 mg DNA vaccine, antibody responses were significantly enhanced with EP as compared to without EP resulting in effective transmission blocking efficiency. Similar immunogenicity enhancing effect of EP was also observed with lower doses (0.5 mg and 1 mg) of DNA plasmids. Further, final boosting with a single dose of recombinant Pfs25 protein resulted in dramatically enhanced antibody titers and significantly increased functional transmission blocking efficiency. Our study suggests priming with DNA vaccine via EP along with protein boost regimen as an effective method to elicit potent immunogenicity of malaria DNA vaccines in nonhuman primates and provides the basis for further evaluation in human volunteers.

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Section: Discussionmentioning

confidence: 99%

Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons

Kumar

Nyakundi

Kariuki

et al. 2013

Vaccine

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show abstract

“…The variable presence of maternal antibodies is the hurdle to overcome to reduce measles mortality among the very young. The use of DNA vaccines (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50); non-MV vectors expressing H, F, and/or N (51-57); immune-stimulating complexes incorporating the H and F proteins (57); or a combination of these strategies (58) has been proposed. Vaccination by these methods presumably avoids inhibition by maternal antibodies, and some of these vaccines have indeed proven protective when administered to infant macaques with circulating maternal antibodies.…”

Section: Discussionmentioning

confidence: 99%

Generation of a More Immunogenic Measles Vaccine by Increasing Its Hemagglutinin Expression

Julik

Valle

2016

J Virol

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Imported measles virus (MV) outbreaks are maintained by poor vaccine responders and unvaccinated people. A convenient but more immunogenic vaccination strategy would enhance vaccine performance, contributing to measles eradication efforts. We report here the generation of alternative pediatric vaccines against MV with increased expression of the H protein in the background of the current MV vaccine strain. We generated two recombinants: MVvac2-H2, with increased full-length H expression resulting in a 3-fold increase in H incorporation into virions, and MVvac2-Hsol, vectoring a truncated, soluble form of the H protein that is secreted into the supernatants of infected cells. Replication fitness was conserved despite the duplication of the H cistron for both vectors. The modification to the envelope of MVvac2-H2 conferred upon this virus a measurable level of resistance to in vitro neutralization by MV polyclonal immune sera without altering its thermostability. Most interestingly, both recombinant MVs with enhanced H expression were significantly more immunogenic than their parental strain in outbred mice, while MVvac2-H2 additionally proved more immunogenic after a single, human-range dose in genetically modified MV-susceptible mice. IMPORTANCEMeasles incidence was reduced drastically following the introduction of attenuated vaccines, but progress toward the eradication of this virus has stalled, and MV still threatens unvaccinated populations. Due to the contributions of primary vaccine failures and too-young-to-be-vaccinated infants to this problem, more immunogenic measles vaccines are highly desirable. We generated two experimental MV vaccines based on a current vaccine's genome but with enriched production of the H protein, the main MV antigen in provoking immunity. One vaccine incorporated H at higher rates in the viral envelope, and the other secreted a soluble H protein from infected cells. The increased expression of H by these vectors improved neutralizing responses induced in two small-animal models of MV immunogenicity. The enhanced immunogenicity of these vectors, mainly from the MV that incorporates additional H, suggests their value as potential alternative pediatric MV vaccines. Despite the existence of an effective vaccine, measles virus (MV) infections remain an insidious threat to global health. After decades of reduction in measles-related mortality due to vaccination, this has stalled at between 110,000 and 120,000 deaths/year since 2012. Approximately 20 million people are infected by measles each year, with significant morbidity and up to 1% mortality (1). In 2014, the United States saw the highest number of annual measles cases since native transmission was declared locally eliminated in 2000 (2) and experienced a large multistate outbreak in the first months of 2015 (3).Protecting young infants against measles is an important goal to attain to improve the current MV vaccine (4). The highest fatality rates due to MV infection occur in infants Ͻ1 year of age (5). Ironically, incre...

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“…Although NHPs are a helpful model, vaccine-induced reactogenicity and efficacy in infant NHPs can diverge from those observed in human infants (46). In addition, as 3M-052 likely exerts its adjuvant effects at local sites of injection (not the systemic bloodstream), our knowledge of it's PD (i.e., the concentration required to achieve an adjuvant effect) is limited by the fact that (a) our in vitro whole blood assay system may not reflect the concentration needed at the injection site (e.g., i.m.)…”

Section: Figure 4 In Vivo Adjuvanticity Of 3m-052 Is Dose Dependentmentioning

confidence: 99%

TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth

et al. 2017

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Poor Immune Responses of Newborn Rhesus Macaques to Measles Virus DNA Vaccines Expressing the Hemagglutinin and Fusion Glycoproteins

Cited by 9 publications

References 46 publications

Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons

Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons

Generation of a More Immunogenic Measles Vaccine by Increasing Its Hemagglutinin Expression

TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth

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